One of the most central and discriminating processes in all living cells is achieved by specific interaction between DNA and protein. Many cellular regulations depend on the fidelity of such specific interactions. Lack of such fidelity can cause cell abnormality. However at the present time we know very little about the detailed mechanisms of such interactions at atomic and structural levels. Even some of the basic questions are not answered: Is it necessary to open up the base pairs for protein to specifically recognize the DNA sequence? Is there a conformational change in protein and/or DNA when it recognizes specific sequences of DNA? How does a protein discriminate between a specific DNA sequence and a similar sequence? Is there a 3rd element, such as water molecules or metal ions, that participates in the specific recognition process? What kind of architectural design should a protein have to be able to "track" along the DNA strand until it finds a specific sequence? Our overall objective is to answer these questions studying EcoRI restriction system and other related questions using X-ray crystallography and conformational analysis. Second line of proposed studies is to determine crystal structure of DNA-RNA hybrid, a prerequisite for DNA replication and a transcription intermediate, and to do structural studies on double helix-double helix contacts, a structural feature necessary to understand DNA/RNA packaging.